January 4, 2012

SAN FRANCISCO – Both sorafenib and transcatheter arterial chemoembolization/radiofrequency ablation can extend the lives of patients with infiltrative hepatocellular carcinoma, according to a retrospective review of 155 patients.

The radiologic-based therapy gave patients a median of 3 additional months of life; sorafenib (Nexavar) gave them a median of 4.5 months. The difference between treatments was not statistically significant.

Little research has been done on infiltrative hepatocellular carcinoma (HCC), including whether it responds to treatment. "Often [patients] are deemed not to be treatment candidates. I think we’ve shown that if you treat these patients, they have a significantly lengthened life. It’s not a huge difference, but it can be decent," said lead investigator Dr. Neil Mehta, a gastroenterology fellow at the University of California, San Francisco.

Perhaps 10% of hepatocellular carcinomas are infiltrative; these tumors are usually larger, with poor definition and vascular invasion.

Just 30% of the 155 patients were treated for their tumors, including the 22 treated with transcatheter arterial chemoembolization/radiofrequency ablation (TACE/RFA) and the 11 treated with sorafenib.

These low treatment rates are not unusual. Patients might be too sick, or may opt out of treatment, Dr. Mehta said. Sometimes it’s thought that the tumor won’t respond, he added.

Treatment did appear to make a difference at UCSF, however. Eleven (50%) of the TACE/RFA patients were alive at 6 months and 4 (18%) were living at 12 months; their median survival was 6 months. Eight (73%) of the sorafenib patients were alive at 6 months, with 4 (36%) alive at 12 months; their median survival was 7.5 months. Only 17% of the untreated patients were alive at 6 months, and 2% at 12 months; their median survival was 3 months.

"Tumor-directed therapy confers a significant survival benefit even after adjusting for factors that may affect treatment eligibility," the researchers concluded. Treatment approaches in the study included liver resection, transplant, and other chemotherapy regimens.

Besides lack of treatment, predictors of death within 6 months were advanced liver disease (Child-Pugh class B or C), alpha-fetoprotein greater than 1,000 ng/mL, large tumor size, and female gender.

Patients ranged in age from 22 to 89 years, and almost 80% were men. Seventy-one percent had stage C disease in the BCLC (Barcelona Clinic Liver Cancer) classification system, whereas 23% had stage D disease, and the rest had stage A or B.

The baseline median alpha-fetoprotein was 347 ng/mL and the median MELD (Model for End-Stage Liver Disease) score was 13. The median maximal tumor diameter was 11.9 cm; 48% of patients had extrahepatic metastases, and 26% had biliary dilation. Hepatitis C was thought to be the cause of liver disease in well over half of patients, followed by hepatitis B, alcoholism, and fatty liver disease.

Dr. Mehta said he had no disclosures. Coauthor Dr. Nicholas Fidelman disclosed grant/research support from Bayer Inc., maker of sorafenib, and Nordion Inc., maker of TheraSphere, a radioembolization product for unresectable HCC.

LONDON (Reuters) - A new vaccine against the chronic liver disease hepatitis C has shown promising results in an early-stage clinical trial in humans, British and Italian scientists said Wednesday.

They said the experimental vaccine, which is based on a modified cold virus and was safety-tested in 41 people, generated immune responses similar to those seen in people who have a rare but natural defense against the disease.

The results suggest it might be possible in future to develop a potentially long-lasting vaccine that would be broadly effective against hepatitis C - a virus estimated to infect around 170 million people worldwide.

But the researchers, whose findings were published in the Science Translational Medicine journal Wednesday, cautioned that much more research is needed over many years before a successful vaccine could be fully developed.

"We've found that it's possible to prime large cellular immune responses against hepatitis C that last for at least a year," said Paul Klenerman of Britain's Oxford University, who led the first trials of the vaccine in humans.

"The immune responses we've seen are exciting and we are beginning the next stage of trials," he said in a statement about the results, adding: "It could be a long road."

Hepatitis C is caused by a virus transmitted through the blood. Those infected can have it for years without symptoms, but if left untreated it can lead to cirrhosis, liver cancer and death.

The mainstay of hepatitis C treatment has been a combination of the generic medicines interferon and ribavirin, but they have only around a 50 percent success rate and interferon can cause flu-like symptoms that mean many patients stop their treatment.

New drugs, including Incivek from Vertex Pharmaceuticals and Merck's Victrelis, were licensed in 2011 and are proving popular, but they still need to be taken with interferon and ribavirin.

Because hepatitis C is a virus that constantly changes, it is a tricky target for designing a vaccine and no successful shot against the infection has yet been developed. There are also six different strains of the virus, making it difficult to make vaccine that works for all types.

The team worked with researchers from Britain's Birmingham University and from Okairos, a small Italian biotech firm, on a new approach to developing a vaccine by stimulating a different part of the immune system from those tried before.

The new vaccine, the researchers explained, is designed to generate a response in the immune system's T-cells to the internal parts of the virus, which are more constant, rather than trying to prime an antibody attack on the virus's ever-changing outer coat.

"The outside shell of the hepatitis C virus is very variable but the inside of the virus is much more stable. That's where the engine of the virus is, where we may be able to successfully target many of the crucial pieces of machinery," said Klenerman.

The team tested the vaccine in a so-called Phase I study designed primarily to gauge the vaccine's safety. A total of 41 healthy adults took part in the study and results showed the vaccine appeared safe and was able to stimulate a large T-cell response against hepatitis C that lasted for at least a year.

The Oxford researchers are starting trials to see if the vaccine can help treat people already infected with hepatitis C, as well as continuing to develop the vaccine to get better immune responses.

"T-cell responses often become weak in those with chronic hepatitis C infections," Klenerman said. "It may be that using a vaccine to boost their immunity could become part of any treatment with other drugs."

A separate research team in the United States is also planning a larger trial in at-risk groups to see if the vaccine can protect against hepatitis C infection, he said.

Abstract

Boceprevir and telaprevir are the first two protease inhibitors available for the treatment of patients infected with hepatitis C virus (HCV) genotype 1. A sustained virological response (SVR) of 70–80% is observed when either of these protease inhibitors is utilized with pegylated interferon (PEG-IFN) and ribavirin (RBV) in treatment naïve patients. Both agents are also highly effective in patients who failed to achieve a SVR during previous treatment with PEG-IFN/RBV. A rapid virological response (RVR) is observed in 56–60% of treatment naïve patients. Patients who achieve a RVR can be treated with a shorter course of therapy (24–28 weeks) and still achieve a SVR rate of 90% or higher. Patients who do not achieve a RVR, those with cirrhosis and certain prior non-responders should be treated for 48 weeks. Although the SVR rates observed with boceprevir and telaprevir are quite similar both globally and within sub-populations, the treatment algorithms for the two agents are unique. The decision of which protease inhibitor to use should assess several factors including the treatment scheme, duration of therapy, adverse event profile, cost and the likelihood of achieving a RVR. The latter is highly dependent upon IFN sensitivity and the IL28B genotype.

Boceprevir and telaprevir were the first two and are currently the only protease inhibitors to be approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of patients infected with hepatitis C virus (HCV) genotype 1. For the past decade, only 40–45% of these patients achieved a SVR when treated with PEG-IFN/RBV [1, 2, 3, 4]. The duration of therapy was for a fixed 48 weeks. In contrast, when either of these two protease inhibitors is added to PEG-IFN/RBV, the SVR rate in treatment naïve patients increases to 70–80% [5, 6, 7]. Boceprevir and telaprevir are also highly effective in patients who fail to achieve a SVR during previous treatment with PEG-IFN/RBV [8, 9]. The availability of these two protease inhibitors has therefore revolutionized the treatment of chronic HCV. For the first time, physicians can tell their patients that it is much more likely they will be ‘cured’ of HCV following treatment.

It has been recognized in recent years that the likelihood of achieving a SVR during treatment with PEG-IFN/RBV was directly related to when the patient became HCV RNA undetectable during therapy [10]. Patients with a RVR, who became HCV RNA undetectable within 4 weeks after initiating treatment, had SVR rates in the 85–90% range and several studies strongly suggested that these patients could receive only 24 weeks of PEG-IFN/RBV [11, 12, 13, 14]. This observation forms the cornerstone of response guided therapy (RGT) [10, 15, 16]; a concept that was readily incorporated into the treatment schemes developed for boceprevir and telaprevir.

This manuscript will review data from the phase 3 clinical trials performed with boceprevir and telaprevir in the treatment naïve population [5, 6, 7] and in patients who previously failed to achieve a SVR with PEG-IFN/RBV [8, 9]. We conclude by discussing issues that may lead to the selection of a specific protease inhibitor. Throughout this discussion, the reader must keep in mind that the phase 2 and 3 clinical trials that led to the approval of boceprevir and telaprevir were each performed against a placebo control (with PEG-IFN/RBV) and that these two protease inhibitors have never been directly compared. It is therefore impossible to conclude that either protease inhibitor is universally superior for the treatment of patients with chronic HCV genotype 1.

Telaprevir

Three phase 3 clinical trials led to the approval of telaprevir, PEG-IFN/RBV for the treatment of patients with chronic HCV genotype 1 [6, 7, 9]. The ADVANCE study was a randomized placebo controlled trial designed to compare 8 weeks vs 12 weeks of telaprevir triple therapy (with PEG-IFN/RBV). Patients who achieved a RVR and remained HCV RNA undetectable throughout the first 24 weeks of treatment were referred to as having an extended RVR (eRVR). These patients were treated for a total of 24 weeks: 8 or 12 weeks of telaprevir-based triple therapy followed by an additional 16 or 12 weeks of PEG-IFN/RBV respectively. Patients who failed to achieve an eRVR received a total of 48 weeks of treatment (8 or 12 weeks of telaprevir-based triple therapy followed by 36 weeks of PEG-IFN/RBV). Patients who received 12 weeks of telaprevir had about a 5% higher SVR rate compared to patients who received only 8 weeks whether they achieved an eRVR and received 24 weeks of treatment (89 vs 83%) or they failed to achieve an eRVR and received 48 weeks of treatment (54% vs 50%). The conclusion of ADVANCE was that 12 weeks of telaprevir was superior and preferable to 8 weeks.

The ILLUMINATE study was a randomized controlled trial designed to compare 24 vs 48 weeks of treatment in patients with an eRVR. All patients were treated with telaprevir-based triple therapy for 12 weeks and then continued PEG-IFN/RBV. Patients who achieved an eRVR were randomized to receive a total of 24 weeks of treatment (12 weeks of telaprevir-based triple therapy plus 12 weeks of PEG-IFN/RBV) or a total of 48 weeks of treatment (an additional 36 weeks of PEG-IFN/RBV). The SVR rates in these two groups were identical (92 vs 90% respectively). Patients who did not achieve an eRVR but did become HCV RNA undetectable by treatment week 24 were treated for a total of 48 weeks. The SVR rate in these patients was 64%. The conclusion of ILLUMINATE was that patients with an eRVR should be treated for only 24 weeks. In both ADVANCE and ILLUMINATE, about 60% of patients treated with telaprevir-based triple therapy achieved an eRVR.

The REALIZE study was a randomized, placebo-controlled trial designed to document the impact of telaprevir-based triple therapy in patients who had failed to achieve a SVR during previous treatment with PEG-IFN/RBV and to determine if 4 weeks of lead-in therapy with PEG-IFN/RBV affected SVR. Patients were randomized to receive ether 12 weeks of telaprevir-based triple therapy followed by 36 weeks of PEG-IFN/RBV or 4 weeks of PEG-IFN/RBV lead-in followed by 12 weeks of telaprevir-based triple therapy, followed by an additional 30 weeks of PEG-IFN/RBV. Both groups were treated for a total of 48 weeks. Overall, the SVR rates in patients with prior relapse, partial response and non-response were 86, 58 and 32% respectively. No significant difference in SVR was apparent between the two treatment arms in any of the three non-responder categories. The conclusion of REALIZE was that 4 weeks of a PEG-IFN/RBV lead-in prior to adding telaprevir did not influence SVR.

The most common adverse events in patients who received telaprevir-based triple therapy compared to PEG-IFN/RBV in these phase 3 clinical trials included anaemia, nausea, diarrhoea, anal-rectal discomfort, rash and pruritus. The average decline in haemoglobin during telaprevir-based triple therapy was approximately 1 g/dl more than that observed with PEG-IFN/RBV; and nearly 40% of patients had a decline in haemoglobin to below 10 g/dl. Over half the patients receiving telaprevir developed a rash and once this occurred it generally worsened over time. In most cases, this was mild-moderate in severity and could be managed symptomatically. Severe rash requiring premature discontinuation of telaprevir occurred in 7% of patients.

The recommended treatment paradigm for telaprevir is illustrated in Fig. 1. Telaprevir is initiated along with PEG-IFN/RBV for the first 12 weeks of treatment. Patients then continue PEG-IFN/RBV for a total of either 24 or 48 weeks based upon the concepts of RGT [14, 15]. Patients who are treatment naïve or with prior relapse to PEG-IFN/RBV can be treated for only 24 weeks if they achieve eRVR. These patients achieve SVR rates that exceed 90%. In contrast, patients who become HCV RNA undetectable after week 4 should be treated for a total of 48 weeks (12 weeks of telaprevir-based triple therapy and 36 weeks of PEG-IFN/RBV). These patients achieve SVR rates of about 64%. It is recommended that all patients with cirrhosis also be treated for 48 weeks. Treatment should be discontinued in any patient with an HCV RNA level of >1000 IU/ml at treatment weeks 4 or 12 and any detectable HCV RNA at treatment week 24.

Figure 1.Treatment paradigm recommended by the FDA for telaprevir. (A) Treatment naïve and patients with prior relapse. (B) Patients with prior partial response, null response and all patients with cirrhosis. Hepatitis C virus (HCV) RNA is tested at week 4. If HCV RNA is undetectable and remains undetectable at week 12 and 24, the patient requires only 24 weeks of treatment. If HCV RNA is under 1000 (log10 3) IU/ml at weeks 4 and 12 and undetectable for HCV RNA at week 24 the patient should be treated for 48 weeks. Therapy is stopped if HCV RNA is greater than log10 3 (1000 IU/ml) at treatment weeks 4 and 12 and any detectable HCV RNA at week 24.

Boceprevir

Two phase 3 clinical trials led to the approval of boceprevir, PEG-IFN/RBV for the treatment of patients with chronic HCV genotype 1 [5, 8]. The SPRINT-2 study was a randomized placebo-controlled trial performed in treatment naïve patients and designed to compare RGT to a fixed 48 weeks of treatment. Patients randomized to the 48 week treatment arm received a 4 week lead-in with PEG-IFN/RBV followed by 44 weeks of boceprevir-based triple therapy (48 weeks of total treatment). Patients randomized to the RGT arm received the 4 week PEG-IFN/RBV lead-in followed by 24 weeks of boceprevir-based triple therapy. Patients who achieved RVR (HCV RNA undetectable 4 weeks after the addition of boceprevir; 8 weeks after the start of treatment) and remained HCV RNA undetectable through week 24 received a total of 28 weeks of treatment (4 weeks of PEG-IFN/RBV and 24 weeks of boceprevir-based triple therapy). Patients who became HCV RNA undetectable more than 4 weeks after the addition of boceprevir and before treatment week 24 received an additional 20 weeks of PEG-IFN/RBV for a total treatment duration of 48 weeks (4 weeks of PEG-IFN/RBV, 24 weeks of boceprevir triple therapy and 20 weeks of PEG-IFN/RBV). The SVR rate achieved with the RGT approach was identical to that observed in patients who received 48 weeks of therapy (70 vs 71%). Patients who achieved a RVR had SVR rates of 96% with 28 weeks of total treatment. Patients who did not achieve a RVR but became HCV RNA undetectable after treatment week 8 (4 weeks after the start of boceprevir) had SVR rates of about 70% when treated for 48 weeks. The conclusion of SPRINT-2 was that the duration of HCV treatment should be determined according to the principles of RGT. Approximately 60% of patients achieved a RVR and could be treated for the shorter duration.

The RESPOND-2 study was a randomized placebo-controlled trial conducted in patients with a prior partial virological response or relapse to PEG-IFN/RBV. The study was designed to document the SVR rate with boceprevir triple therapy retreatment and like SPRINT-2 to compare RGT to a fixed 48 weeks of treatment. Although patients with documented prior non-response were not enrolled in this study a significant proportion of the patients had less than a 1 log10 decline in HCV RNA during the 4 week lead-in and thus behaved biologically as non-responders. Patients were randomized to receive either 48 weeks of treatment (4 weeks PEG-IFN/RBV lead-in and 44 weeks of boceprevir-based triple therapy) or RGT. Patients randomized to the RGT arm received the 4-week PEG-IFN/RBV lead-in followed by 32 weeks of boceprevir-based triple therapy. Patients who achieved RVR (HCV RNA undetectable 4 weeks after the addition of boceprevir; 8 weeks after the start of treatment) and remained HCV RNA undetectable through week 24 received a total of 36 weeks of boceprevir-based triple therapy (4 weeks of PEG-IFN/RBV and 32 weeks of boceprevir-based triple therapy). Patients who became HCV RNA undetectable more than 4 weeks after the addition of boceprevir and before treatment week 24 received an additional 12 weeks of PEG-IFN/RBV for a total treatment duration of 48 weeks (4 weeks of PEG-IFN/RBV, 32 weeks of boceprevir triple therapy and 12 weeks of PEG-IFN/RBV).

The SVR rate in patients with prior relapse was 72%. Patients who were sensitive to interferon and had more than a 1 log10 decline in HCV RNA during the 4 week lead-in had an SVR rate of 76%. Patients who were insensitive to interferon and had less than a 1 log10 decline in HCV RNA during the 4 week lead-in had a SVR of 32%. No significant differences in SVR rates were evident between a fixed 48 week treatment and the RGT approach. Patients who achieved RVR (HCV RNA undetectable 4 weeks after the addition of boceprevir) had SVR rates of 88% with the shorter duration of therapy. Patients who did not achieve RVR but became HCV RNA undetectable after treatment week 8 (4 weeks after the start of boceprevir) had SVR rates of about 75% when treated for 48 weeks. The conclusion of RESPOND-2 was that the duration of HCV treatment should be determined by the principles of RGT even in patients with prior non-response to PEG-IFN/RBV.

The most common adverse events in patients who received boceprevir-based triple therapy compared to PEG-IFN/RBV in these phase 3 clinical trials included anaemia and dysgusea. The average decline in haemoglobin during treatment with boceprevir-based triple therapy was approximately 1 g/dl greater than that observed with PEG-IFN/RBV; nearly half had a decline in haemoglobin to below 10 g/dl. Although 43% of patients in these two phase 3 clinical studies received epoetin alfa to treat anaemia, no significant difference in SVR rates was observed between patients who received epotin alfa and those patients whose anaemia was managed by ribavirin dose reduction.

The recommended treatment paradigm for boceprevir is illustrated in Fig. 2. Boceprevir is initiated after 4 weeks of lead-in therapy with PEG-IFN/RBV. After the 4 week lead-in, patients are treated with boceprevir triple therapy. Patients who are HCV RNA undetectable at treatment week 8 (an RVR 4 weeks after adding boceprevir) and remain HCV RNA undetectable at treatment weeks 12 and 24 can be treated for a total of 28 weeks (4 weeks of PEG-IFN/RBV lead-in and 24 weeks of boceprevir-based triple therapy). These patients have SVR rates which exceed 90%. In contrast, patients who become HCV RNA undetectable more than 4 weeks after the addition of boceprevir (after treatment week 8) should be treated for a total of 48 weeks. This consists of 4 weeks of PEG-IFN/RBV lead-in, 32 weeks of boceprevir triple therapy and another 12 weeks of PEG-IFN/RBV. These patients achieve SVR rates of about 70%. It is recommended that patients who are interferon resistant (less than a 1 log10 decline in HCV RNA during the lead-in), prior non-responders and patients with cirrhosis receive 44 weeks of boceprevir-based triple therapy following the 4 week PEG-IFN/RBV lead-in. Treatment should be discontinued in patients with an HCV RNA level of >100 IU/ml at treatment week 12 and any detectable HCV RNA at treatment weeks 24.

Figure 2.Treatment paradigm recommended by the FDA for boceprevir. (A) Treatment naïve. (B) Patients with prior relapse and partial response. (C) Patients with prior null response, interferon insensitivity as assessed by lead-in and all patients with cirrhosis. Hepatitis C virus (HCV) RNA is tested at week 8. If HCV RNA is undetectable and remains undetectable at week 24 the patient requires only 28 weeks of treatment. If HCV RNA is positive for HCV RNA at week 8, under 100 (log10 2) IU/ml at week 12 and undetectable at week 24 the patient should be treated for 48 weeks. Therapy is stopped if HCV RNA is greater than log10 2 (100) IU/ml at treatment week 12 and any detectable HCV RNA at week 24. * HCV RNA may also be measured at week treatment 4, at end of lead-in, to assess interferon sensitivity. In patients with prior null response, interferon insensitivity and cirrhosis who are treated for 48 weeks there is no formal stopping rule for being HCV RNA detectable at week 24. However, most experts would stop treatment if HCV RNA were still positive at this time.

Interferon sensitivity

In patients who fail treatment, several interferon-stimulated genes are upregulated before treatment, indicating a blunted response to interferon [17]. At least some degree of interferon sensitivity is necessary for patients to achieve SVR and those who are interferon insensitive are at risk of having protease-resistant strains of HCV emerge during treatment [18, 19]. Interferon sensitivity is largely a genetic trait of the host and this is modulated by nucleotide polymorphisms within the interleukin (IL) 28B gene. Patients who have cytosine-cytosine (CC) at a specific site within this gene are highly sensitive to interferon [20, 21, 22]. Nearly 80% of these patients achieve RVR, can be treated for a shorter duration with either boceprevir or telaprevir-based triple therapy and enjoy SVR rates that exceed 90% [23, 24]. In contrast, patients with thymidine-thymidine (TT) at this specific site within the IL28B gene are far less sensitive to interferon. Only about 50% of these patients will achieve a RVR and could be treated for a shorter duration. The interferon sensitivity and response characteristics of patients with IL28B-CT fall somewhere between these two extremes. Patients who do not become HCV RNA undetectable during treatment with boceprevir or telaprevir triple therapy are at high risk of developing protease resistant virus [5, 18, 19].

Approximately 15% of all patients with HCV genotype 1 achieve a RVR when treated with PEG-IFN/RBV [10, 16]. Most of these patients have IL28B genotype CC [21]. Patients who achieve a RVR with PEG-IFN/RBV also have very high SVR rates which vary from 85 to 95% in most studies [12, 13, 14]. Recognizing that patients with RVR could be treated for only 24 weeks with an IFN containing regimen is one of the cornerstones of RGT [10, 15, 16].

Differences in the treatment paradigm

The paradigms utilized to treat chronic HCV with boceprevir and telaprevir are summarized and compared in Table 1. Telaprevir is started with PEG-IFN/RBV at the onset of therapy and used for only 12 weeks. In contrast, boceprevir is initiated after the 4 week PEG-IFN/RBV lead-in. Measuring HCV RNA after 4 weeks of treatment with PEG-IFN/RBV makes it possible to assess interferon responsiveness, the likelihood of SVR and the emergence of resistance after boceprevir is added. In both the telaprevir and boceprevir studies patients who were HCV RNA undetectable at treatment week 4 had very high and nearly identical SVR rates whether treated with PEG-IFN/RBV or with protease inhibitor triple therapy [5, 6]. Do patients who are already HCV RNA undetectable at the conclusion of the 4 week PEG-IFN/RBV lead-in really need a protease inhibitor? Only the lead-in treatment paradigm provides the opportunity to avoid the additional adverse events of a costly protease inhibitor in patients who have a high likelihood of achieving a RVR.

Selecting a paradigm for treatment of HCV

The factors used to select a protease inhibitor include efficacy, the duration of protease inhibitor administration, the total duration of therapy, the adverse event profile and cost. The efficacy of these two agents is summarized in Table 2. For treatment naïve patients, the rates of SVR appear very similar in patients who achieve a RVR (89–96%) and in patients with a delayed virological response who become HCV RNA negative more than 4 weeks after the initiation of the protease inhibitor (64–75%). A similar percentage of treatment naïve patients achieve a RVR (56–60%) and can be treated for a shorter duration. When divided by IL28B status, SVR rates also appear to be quite similar [23, 24]. Response rates are more difficult to compare in the retreatment population because true non-responders were not evaluated in the RESPOND-2 study. However, if one accepts that patients who are IFN insensitive during the lead-in are biologically similar to non-responders [4] than similar rates of SVR are observed during retreatment as well.

The duration of protease inhibitor administration and the treatment paradigm are no doubt more streamlined with telaprevir. All patients begin telaprevir and PEG-IFN/RBV at the onset of treatment, receive 12 weeks of telaprevir and either 24 or 48 weeks of PEG-IFN/RBV. In contrast, the initiation of boceprevir is delayed by 4 weeks and is administered for 24, 32 or 44 weeks, whereas PEG-IFN/RBV IL combination is administered for 28, 32 or 48 weeks respectively. In contrast, boceprevir may have a somewhat more tolerable adverse event profile. Both agents exacerbate the anaemia of PEG-IFN/RBV to a similar extent. However, telaprevir is associated with a rash in over 50% of patients and several gastrointestinal symptoms.

The final issue that could be considered is cost. The published cost for telaprevir is just under 50 000 USD for 12 weeks of medication. The published cost of boceprevir is 1100 USD per week or $26 400, $35 200 or $48 400 for 24, 32 and 44 weeks of treatment respectively. The costs of treatment are therefore similar in patients who require 32–44 weeks of boceprevir. In contrast, the cost of therapy is considerably reduced in patents who achieve a RVR and receive only 24 weeks of boceprevir. This reduced cost is possible in most patients with IL28B genotype CC who have high rates of RVR [23, 24]. In addition, approximately 30% of patients with this IL28B genotype are already HCV RNA undetectable by the end of the 4 week lead-in with PEG-IFN/RBV alone. Simply continuing these patients on PEG-IFN/RBV will yield SVR rates that are similar to those observed with either telaprevir or boceprevir triple therapy without any additional cost [5, 6]. Such a strategy is certainly reasonable in countries or in patients with limited financial resources.

Conflicts of interest

Dr Shiffman has received consulting fees from Conatus, Genentech/Roche, Human Genome Sciences and Romark; has attended advisor meetings with Bristol Myers-Squibb, Gilead, Merck, Pfizer, Vertex and Zymogenetics; has received grant support from Abbott, Achillion, Anadys, Conatus, Genentech/Roche, Gilead, Globeimmune and Zymogenetics; has provided lectures on behalf of Genentech/Roche, Merck and Vertex; and has served on a Data Safety Monitoring Board for Anadys and Abbott.

Abstract

Due to the side effect profile of pegylated interferons interferon treatment has become the holy grail of drug development for chronic hepatitis C. The precise role of interferon in treatment of hepatitis C is not fully understood, besides its antiviral effects interferon is an immune modulator. Nevertheless, recent proof of concept studies indicated, that cure of chronic hepatitis C can be achieved without interferon. Various compounds achieved this goal, like the polymerase inhibitor PSI 7977, the combination of NS5a inhibitor (daclatasvir) and a protease inhibitor (asunaprevir) and the cyclophillin antagonist alisporivir. Various other combinations are investigated currently. Providing that phase 3 studies will confirm these exciting data, direct acting antivirals or host targets will replace peginterferon/ribavirin combination therapy.

The current standard of care (SoC) for treatment of chronic hepatitis C is still a combination of a pegylated interferon-α2 (PEG-IFN) with ribavirin (RBV) [1]. Recently, the first two direct-acting antivirals (DAA) were licensed in the USA and the European Union. In combination with PEG-IFN/RBV, telaprevir and boceprevir significantly increases the rate of cure of chronic hepatitis C, genotype 1, both in naïve and treatment-experienced patients [2, 3, 4]. Nevertheless, treatment is still restricted to patients who can tolerate PEG-IFN and RBV. As many as 50% of patients, including those with the greatest need of effective treatment such as those with advanced liver disease, cannot receive the new triple therapy. Thus, an interferon-free treatment regimen is required .

Investigation of DAA combination regimens has exploded in the last 12 months. This is possible because of the diversity of antiviral mechanisms besides protease inhibitors that are now in Phase II of the drug development pipeline for hepatitis C [5]. Diverse mechanisms are important because they often have different resistance profiles, and antiviral combinations are being assembled with new compounds with non-overlapping profiles to provide a greater barrier to antiviral resistance. Other factors that are important when assembling optimal combinations include the safety and tolerability profile of each agent, compatible pharmacokinetic profiles and a low potential for unfavourable drug–drug interactions.

The role of interferon in the treatment of chronic hepatitis C

Although interferon (IFN) has been used to treat chronic hepatitis C for more than 25 years, its precise role in eradicating the hepatitis C virus (HCV) still remains unknown. Determining the mechanism(s) involved in an IFN-induced cure is mandatory if IFN-free treatment regimens are to be developed. IFNs play a pivotal role in the outcome of a viral infection. IFNs are a family of pleiotropic cytokines that typically exhibit antiviral, antiproliferative, antitumour and immunomodulatory properties. The first response of an organism to intruding pathogens is an inflammatory reaction that includes secretion of cytokines and chemokines. These signalling molecules activate or attract innate immune cells, such as neutrophils, macrophages, natural killer (NK) cells, and dendritic cells (DCs), to orchestrate an effective response at the site of infection. Induction of innate immune mechanisms is not pathogen-specific, but is dependent upon interactions between pathogenic factors and host-cell determinants. During viral infection, some of the most prominent cytokines produced are IFNs. The importance of IFNs goes beyond their antiviral activities and includes numerous immunoregulatory functions that affect both innate and adaptive immunity [6]. IFN-induced clearance of HCV is both cytolytic (clearance of HCV-infected hepatocytes) and non-cytolytic (intra-cytoplasmic destruction of HCV without cell injury).

Innate immunity can be principally affected by HCV at the level of both: (i) type I IFN production by infected hepatocytes and (ii) the signals provided by the relative receptors (IFNAR-1/2) once they are engaged by soluble type I IFNs (mainly produced by plasmacytoid dendritic cells). If these defects are combined with a low viral load or infection by HCV strains that are highly susceptible to the antiviral effects of IFN, the spread of the HCV virus is contained, and the functions of dendritic cells, NK, B and T cells would not be heavily affected. Induction of type I IFN production in HCV-infected cells (i.e. hepatocytes) either on contact with TLR3 in the endosomal compartments, or upon recognition of the polyuridine motif of the HCV 30 untranslated region (UTR) by the retinoid acid-inducible gene I (RIG-I) in the cytoplasm, may be affected by HCV [7, 8, 9]. Thus, the initial response to HCV infection might not be sufficient to induce effective primary or secondary CD8 T-cell responses [10]. In chronic HCV infection, two major pathways, T-cell exhaustion and viral escape, contribute to CD8+ T-cell failure. In vivo models of HCV infection demonstrate selective impairment of T cells infiltrating HCV-infected livers because of the high concentrations of viral proteins produced at the site of infection, which may play a role in HCV persistence by affecting local adaptive immune responses [9].

The immunomodulatory activity of PEG-IFN-α and RBV induced T-cell immune responses may be important to eliminate chronic HCV infection [11]. In a prospective study, the kinetics of T-cell responses to HCV antigens (NS3-4 and core) correlated with virological outcome in patients undergoing PEG-IFN-α2a/RBV therapy. NS3-4-directed T helper cell type 1 (Th1) responses were detected in 77% of patients with a significant decline in viremia at treatment week 4, but were not detected in those with a slower viral decline. HCV-specific T-cell reactivity was uncommon at baseline, but increased markedly during antiviral therapy, peaking at around treatment weeks 4–8. Resolution of hepatitis C viremia was significantly more likely in patients who developed HCV-specific T-cell proliferation with increased IFN-gamma production [12]. The detectability of NS3-4-directed Th1 responses was associated with faster viral clearance, was short-lived and was not associated with the final treatment outcome [13]. This may be explained because HCV abolishes the blockade of the adaptative immune response by inhibiting viral replication. T-cell activation was transient, but not always sufficient to clear infected hepatocytes. Thus, if rapid inhibition of HCV replication by DAA is sufficient to restore adaptative immunity, exogenous IFN administration may not be necessary.

The other important role of IFN is the inhibition of viral replication. In drugs with a low genetic barrier such as first generation protease inhibitors, IFN and RBV are required to block the emergence of DAA resistant viral strains [14, 15]. Potential strategies to overcome this problem are: (i) DAA combinations including polymerase inhibitors with a high barrier to resistance; (ii) triple DAA therapy; and (iii) combinations of two DAAs with a lower genetic barrier to resistance plus RBV. A mathematical model by Perelson et al. [16] suggests that IFN-free regimens will need to contain three or four distinct antiviral mechanisms to obtain a sustained viral response (SVR) before the development of resistance.

Proof-of-concept studies

The first published trial with an all-oral combination treatment with two experimental anti-HCV drugs [mericitabine, a nucleoside polymerase inhibitor (NI); and danoprevir, an NS3/4A protease inhibitor] in patients with chronic HCV infection was the INFORM-1 study [17]. Patients with chronic hepatitis C, genotype 1, received up to 13 days of oral combination treatment with mericitabine (500 or 1000 mg twice daily) and danoprevir (100 or 200 mg every 8 h or 600 or 900 mg twice daily) or placebo. Eligible patients were sequentially enrolled into one of seven treatment cohorts and were randomly assigned by interactive voice or a web response system to either active treatment or placebo. The primary outcome was a change in HCV RNA concentrations from baseline to day 14 in patients who received 13 days of combination treatment. Eighty-eight patients were randomly assigned to a drug treatment regimen (n = 74 over seven treatment groups; 73 received at least one dose of study drug) or to placebo (n = 14, all of whom received at least one dose). The median change in HCV RNA concentrations from baseline to day 14 ranged from −3.7 to −5.2 log10 IU/mL in the cohorts that received 13 days of combination treatment. At the highest combination doses tested (1000 mg RG7128 and 900 mg danoprevir twice daily), the median change in HCV RNA concentrations from baseline to day 14 was −5.1 log10 IU/mL in treatment-naive patients and −4.9 log10 IU/mL in previous SoC non-responders. The combination of RG7128 and danoprevir was well tolerated with no severe treatment-related or adverse events, no grade 3 or 4 changes in laboratory parameters and no safety-related treatment discontinuations. Virological breakthrough, with the selection of resistant variants, has not yet been observed in short-term clinical studies of the NS3/4A protease inhibitor danoprevir plus the NI, mericitabine, suggesting that inclusion of an NI in DAA combination therapy may be an attractive strategy. However, additional efficacy (SVR) and safety data from longer term treatments are still required. A phase 2a study is ongoing (Matterhorn study).

In another study [18], the combination of the protease inhibitor BI 201335, the polymerase inhibitor BI 207127 and RBV was shown to have a rapid and strong activity against HCV genotype-1 with no severe adverse events. Thirty-two treatment-naïve patients with chronic HCV genotype-1 infection were randomly assigned to groups that were administered 400 or 600 mg BI 207127, three times a day (TID), plus 120 mg BI 201335, once a day and 1000–1200 mg RBV per day for 4 weeks. The primary efficacy endpoint was virological response (HCV RNA < 25 IU/mL at week 4). The virological response rates were 47, 67 and 73% at days 15, 22, and 29, respectively, in the group receiving BI 207127 400 mg TID; a higher response rate was observed in patients with genotype-1b compared with genotype-1a. The virological response rates were 82, 100 and 100%, respectively, in the group receiving BI 207127 600 mg TID, and did not differ among genotypes. One patient in the group receiving 400 mg TID had a virological breakthrough [≥1 log [10] rebound in HCV RNA] at day 22. The most frequent adverse events were mild gastrointestinal disorders, rash and photosensitivity. There were no severe or serious adverse events; none of the patients discontinued treatment early.

The results of a proof-of-concept study for SVR with a PEG-IFN-free treatment regimen in HCV patients was recently reported. Four of eleven genotype 1 patients, who were non-responders to PEG-IFN/RBV treatment, achieved a SVR after 24 weeks of treatment with the combination of an NS5A inhibitor and an NS3/4A protease inhibitor, with only one relapse in this cohort [19], especially in patients with genotype 1b [20]. This suggests that HCV can be eradicated in chronically infected patients with a PEG-IFN-free DAA combination regimen, and supports investigations of various DAA combinations to improve SVR rates without PEG-IFN.

These observations provide a proof-of-concept for an oral approach to the treatment of HCV, including a combination of DAA without PEG-IFN.

ZENITH is an ongoing Phase 2 study of multiple 12- and 24-week response-guided treatment regimens with VX-222 (400 or 100 mg), a polymerase inhibitor in development, in combination with telaprevir [21]. The all-oral treatment arms (VX-222 400 or 100 mg plus telaprevir 1125 mg BID) were discontinued because of a pre-defined stopping rule in relation to viral breakthrough. The two treatment arms including PEG-IF and RBV (quadruple therapy) could stop all treatments at week 12, if hepatitis C virus was undetectable at weeks 2 and 8. Twenty-six of fifty-nine (44%) patients qualified for 12 weeks of therapy, and 88.4% of these had a SVR. The remaining patients received an additional 12 weeks of PEG-IFN/RBV. SVR was achieved in 96%. The overall SVR rate was 86.4%.

Another approach is the combination of nucleoside polymerase inhibitors (PSI-7997 with PSI-938) [22] with promising initial data. The approach of combining three non-cross resistant DAAs with a lower genetic barrier to resistance, i.e. an NNI plus a NS3/4A protease inhibitor and an NS5A inhibitor, is well supported by mathematical analyses. Rong et al. demonstrated that resistant variants against the three drug classes are unlikely to pre-exist before treatment initiation, and emergence is unlikely to occur during therapy [23]. However, drug–drug interaction and overlapping safety profiles remain an issue.

A third highly attractive strategy is to combine two DAA with a lower genetic barrier to resistance, plus RBV. A trial evaluating GS-9256 plus tegobuvir, with or without RBV demonstrated the central role of RBV in the decrease in HCV RNA and the reduction of viral breakthroughs for DAA combinations with a low barrier to resistance. Unfortunately, this study was interrupted because of safety concerns (Table 1).

Finally, a new class of drugs called cyclophilin inhibitors may be used in an IFN-free approach. Alisporivir (DEB025) is the first in this class of drugs, and is currently under investigation. Unlike other compounds under development that target the virus directly, Alisporivir is a host targeting antiviral that targets host proteins essential for the replication of HCV. As these proteins play a key role in the replication of all types of HCV, alisporivir may offer an effective treatment option for a broad range of HCV forms and be effective against other common HCV genotypes. High SVR rates were obtained in combination with PEG-IFN/RBV [24]. INF-free regimens in patients with genotypes 2 and 3 were recently presented [25, 26]. Alisporivir as IFN-free therapy achieves early on-treatment viral response in up to half of G2/3 patients by treatment week 6 and in most patients who reached end of treatment [25]. In a phase 2a study PSI 7977 in combination with ribavirin reached a 100% cure rate in just 12 weeks [26].

Summary

As a result of the side effects of IFN, there is ongoing search for interferon-free antiviral approaches to cure chronic hepatitis C. The FDA, EMA as well as patient advocacy groups are strong proponents of investigating antiviral drug combinations prior to approval of individual components. Although proof-of-concept studies confirm that such approaches may be feasible, at present, only oral combinations together with PEG-IFN/RBV offer the best chances for cure even in non-responders to SoC treatment. The best drug combinations must prevent the emergence of drug resistant viral strains, have a high degree of safety and efficacy, an easy treatment algorithm and short treatment duration. The treatment should work for all genotypes. Although the ideal drug has not yet been found there is an urgent medical need because patients with advanced liver disease or organ transplant patients (excluding liver transplants) cannot tolerate IFN and are in great need of effective treatment.

Conflicts of interest

Dr Ferenci is a member of the global advisory board and of the speaker bureau of ROCHE. He also receives an unrestricted research grant from ROCHE Austria. He is also member of the global advisory boards of Vertex/Tibotec, Böhringer-Ingelheim, MSD and Rottapharm-Madaus, and serves as advisor to Pfizer, Novartis, Achilleon, GSK.

Abstract

Despite the availability of highly effective therapy for hepatitis C virus (HCV) infection, few patients receive treatment. Barriers arising at multiple levels, from diagnosis to specialist referral, may impede the delivery of hepatitis C care. At the patient level, lack of awareness, fear of side effects, poor adherence and comorbid conditions may prevent treatment. For providers, limited knowledge, lack of availability and communication difficulties may be problematic. At the government and payer level, a lack of promotion, surveillance and funding may interfere. Each of these barriers needs to be addressed if wider implementation of antiviral therapy is to be achieved.

Recent advances in the treatment of hepatitis C virus (HCV) infection have produced antiviral therapies capable of higher cure rates and shorter treatment durations. For the 130 million to 170 million persons worldwide with chronic HCV infection, current therapies offer a greater than 60% likelihood of sustained virological response (SVR), regardless of viral genotype [1, 2, 3, 4]. However, for effective therapy to be delivered, long-standing barriers to treatment need to be addressed. Furthermore, with increased costs, higher rates of adverse events, and complicated treatment algorithms, newer agents may present even greater challenges to patients and physicians. An understanding of existing barriers to HCV treatment is important to help guide initiatives aimed at improving treatment rates and, ultimately, outcomes.

Establishing current treatment rates

Only a small minority of HCV-infected persons receives treatment. The proportion of patients treated with antiviral therapy has been estimated in academic, community and Veterans Affairs (VA) hepatitis C cohorts (Table 1). Treatment rates ranged from 1.1% in a Vancouver inner-city population to 30% at a university-affiliated VA [5, 6]. Market research from the USA suggests that less than 10% of persons with known infection have been treated [7]. Likewise, market uptake of interferon (IFN) in Europe indicates an average treatment rate of 3.5% [8]. Treatment rates may be higher among countries where government-sponsored surveillance and treatment programmes are available, such as in France and other European countries [9, 10].

Numerous barriers related to patient, provider, government and payer factors may effectively prevent the delivery of HCV care. These barriers arise at multiple points beginning from the time of infection to the delivery of antiviral therapy (Fig. 1).

Figure 1. Stepwise barriers to hepatitis C treatment.

Patient factors

Patient-related factors are a common source of treatment deferral and include limited awareness, poor adherence to physician recommendations, economic or social pressures, treatment fears, psychiatric disease and injection drug use.

Knowledge and awareness

Between 65% and 75% of patients with chronic HCV infection are unaware of their infection [11], representing the single greatest barrier to treatment. Furthermore, among infected or at-risk persons, knowledge related to HCV is poor. Confusion regarding modes of transmission, disease complications and interpretation of HCV screening tests is common [12, 13, 14]. These deficiencies may contribute to missed treatment opportunities, continued transmission and poorer health outcomes [11].

Non-adherence

Though identification of infection may represent the largest barrier to treatment initiation, patients frequently fail to seek treatment once the diagnosis is established. Among patients referred for evaluation of HCV, between 24% and 57% will not attend their initial subspecialty evaluation [15, 16, 17]. Likewise, patients may demonstrate a lack of adherence to the subsequent evaluation process, missing clinical appointments and failing to obtain recommended diagnostic testing [18]. This finding is recognized by treating physicians, 80% of whom cited patient non-adherence as a barrier to high-quality service in the UK [19]. There are multiple reasons for this lack of adherence. Notably, patients may not recognize the urgency to treat an essentially asymptomatic disease [20]. Furthermore, significant economic and social pressures may contribute.

Economic and social pressures

Persons with HCV are more likely to be uninsured compared with individuals without HCV. Data from the National Health and Nutrition Examination Survey (NHANES III) indicate that 29.6% of HCV-infected patients in the USA are uninsured, compared with 12.2% of persons without infection [21]. Furthermore, uninsured persons are less likely to have contact with a healthcare professional, reducing the likelihood of diagnosis and treatment. Although a lack of health insurance is a major barrier to treatment, economic pressures are not exclusive to the uninsured. A cross-sectional study of HCV patients referred to a tertiary care centre found that one-half of patients cited personal financial resources as a barrier to care, despite 90% of patients possessing medical coverage [22]. Fears of missed work obligations may further contribute to financial insecurity [23].

In addition to financial pressures, patients cite multiple social factors as reasons for deferring therapy. These include family obligations, lack of social support, social rejection and stigmatization [22, 23, 24]. More than half of HCV patients report feeling stigmatized, primarily because of the association between HCV and HIV, promiscuity and/or substance abuse [24, 25]. These patients have higher levels of anxiety, worsened quality of life and difficulty coping [25]. Furthermore, patients may feel stigmatized by their physicians [26], further reducing the likelihood of treatment adherence.

Fears of treatment

For those patients who present for evaluation, fears related to antiviral therapy figure prominently into their decision to pursue treatment. An important consideration among HCV patients is the risk to benefit tradeoff related to treatment [23]. Although a desire to eradicate a chronic, progressive infection may seem intuitive, patients may be unable to look beyond the short-term risks of therapy, particularly side effects. Among patients deferring HCV therapy, nearly two-thirds cite a fear of side effects, coupled with the asymptomatic nature of their disease, as the primary reason for deferral [22]. These findings are supported by an international study of treating physicians, who rated patients’ fear of side effects as the most important barrier to HCV treatment [27]. Similar findings were noted in a survey of UK physicians [19].

Fears of treatment-related side effects are not without merit. Virtually all patients will experience a treatment-related side effect, ranging from mild constitutional symptoms to significant haematological abnormalities. [1, 2, 3, 4]. Adverse effects greatly impact quality of life and may lead to dose reductions and treatment discontinuation. Although these fears are valid, they may also be heightened by the availability of inaccurate or skewed information [28]. Therefore, it is imperative that patients receive appropriate pre-treatment education and counselling to allay such fears.

Psychiatric illness represents a significant barrier to HCV treatment. Adverse psychiatric effects, including irritability, depression and mood swings, are common complications of IFN use. Between 21% and 58% of patients will develop significant depression with IFN therapy [29]. Furthermore, HCV-infected patients have a higher prevalence of pre-existing psychiatric illness [30]. Recognizing the risks of IFN, clinicians frequently defer therapy for patients with underlying psychiatric illness [6]. Unfortunately, these patients are unlikely to obtain treatment after initial deferral [31]. However, the presence of psychiatric illness is no longer considered an absolute contraindication to therapy [29]. When treated with a multidisciplinary approach, including regular psychiatric monitoring, patients with psychiatric disorders can achieve comparable outcomes to those without psychiatric illness [32]. In a randomized, controlled trial, participants initially deferred from therapy because of substance abuse or psychiatric illness were more likely to become eligible for subsequent antiviral therapy after enrollment in a multidisciplinary intervention compared with those receiving standard of care[33].

Injection drug use

Injection drug use is a frequent mode of HCV acquisition, accounting for a high proportion of new cases worldwide and 60% of incidence cases in the USA [29, 34]. Active use of injection drugs is a common reason for HCV treatment deferral [17, 35, 36]. One reason is the high prevalence of depression and psychiatric illness among intravenous drug users (IDUs) [37]. In addition, concerns regarding poor patient adherence, increased risk of adverse effects and post-treatment reinfection may lead to deferral [38]. Intravenous drug users have poor awareness of current treatments, with fewer than half recognizing that HCV is a curable disease [39, 40]. However, between 70% and 80% of IDUs express a willingness for treatment [39, 40, 41]. Furthermore, favourable treatment outcomes have been demonstrated in both active IDUs and those receiving methadone maintenance [32, 42, 43]. Therefore, treatment for these patients should be considered in the setting of close monitoring and adjunctive psychiatric and substance use counselling [29].

Provider factors

Barriers to hepatitis C treatment may arise at the provider level, including primary care physicians and subspecialists. Key barriers to treatment include lack of knowledge and awareness, limited specialist availability and/or lack of referral and communication issues.

Knowledge and awareness

Healthcare professionals have demonstrated key knowledge deficits related to HCV prevalence, risk factors, prevention and management [11]. Among primary care providers, this may be attributable to a lack of experience. In a nationwide survey of primary care physicians, 73% of respondents reported seeing five or fewer HCV patients in the preceding year, with 44% reporting no experience with HCV treatment [44]. Although most physicians correctly identified risk factors for HCV, only 59% reported regular screening for these risk factors. Similar deficiencies in HCV testing have been noted in studies of family practitioners and obstetrics and gynaecology providers [45, 46]. Knowledge of HCV was likewise inadequate among drug-treatment providers [47]. Among patients with HCV, perceived physician incompetence is a known barrier to care [26].

Specialist referral and availability

Primary care physicians infrequently refer HCV patients for subspecialty evaluation. Only one-half of HCV-infected patients are referred to a specialist for evaluation and management [5, 48]. For patients with normal liver tests, the likelihood of referral is below 30% [46]. Furthermore, for those patients referred for treatment, the availability of specialists presents an additional barrier. It is estimated that 80% of chronic HCV patients are managed by 20% of gastroenterologists [7]. Specialists are concentrated within academic medical centres or government-designated Centres of Excellence, limiting the availability of local treatment providers. As a result, patients may face long-distance travel, extended wait times and a lack of scheduling flexibility [19, 49]. Although academic hepatologists may be more adept at managing adverse effects and limiting dose reductions, the number of patients with chronic HCV may exceed their availability [7]. Efforts to expand the availability of specialist expertise via telemedicine have shown promise [50].

Communication issues

Negative interactions with HCV treatment providers may serve as an additional barrier to treatment. In a cross-sectional study of 322 HCV patients treated at a tertiary care centre, 41% reported communication difficulties with their physicians [26]. Specifically, patients felt rushed, misled or not listened to. Patients may question a physician's competence, or feel stigmatized by these interactions. Healthcare workers are known to harbour negative views of injection drug users, characterizing them as manipulative and unpleasant [11]. As a result of these interactions, patients may feel discouraged, less likely to listen to physician recommendations and more inclined to defer therapy.

Government and payer barriers

Governments and payers are critical to delivering HCV services, implementing surveillance programmes, disseminating information and increasing public and provider awareness. Although patient and provider factors receive the greatest attention, obstacles arising at the government and payer level are likewise important. In an international study of HCV providers, lack of treatment promotion and insufficient funding were noted as significant government level barriers [27]. Likewise, lack of insurance coverage, high out-of-pocket expenses and excessive paperwork were cited as payer-level barriers. In a separate study of UK physicians, more than two-thirds of respondents reported inadequate funding as a barrier to quality HCV care [19]. These sentiments were echoed in the recent Institute of Medicine report on the prevention and control of viral hepatitis in the USA [11]. Specifically, the committee noted the poorly developed surveillance system, inadequate educational initiatives and fragmented viral hepatitis services in this country. To address these issues, increased resource allocation and improved collaboration between government, healthcare and educational stakeholders are needed. In the European Union, government sponsored screening and surveillance programmes have greatly increased diagnosis rates of HCV infection[9, 10].

Looking forward: direct acting antivirals

The recent introduction of the direct acting antivirals (DAA) boceprevir and teleprevir has changed the current treatment paradigm for patients with genotype 1 infection. Among treatment-naïve patients, overall SVR rates exceeding 70% are now possible, with the added potential for abbreviated treatment duration [3, 4]. For patients concerned about efficacy and duration, the introduction of these agents may increase treatment appeal. However, these benefits must be balanced against increased treatment complexity, higher rates of adverse events and the potential for drug-drug interactions [51]. It remains to be seen how the availability of triple therapy will influence current treatment barriers.

Conclusions

Multiple barriers to the diagnosis, evaluation and delivery of hepatitis C treatment limit the widespread uptake of antiviral therapy. Although recent advances in HCV treatment offer the potential for high cure rates and shorter treatment durations, long-standing obstacles to treatment must be addressed. Poor awareness, misguided and exaggerated fears, relative contraindications and insufficient funding all contribute to strikingly low treatment rates. Recognizing the global burden of infection, there is a critical need to reduce current barriers to hepatitis C treatment.

Conflicts of interest

Grant Support: CEM is supported by the National Institutes of Health T32 DK07634. MWF is supported in part by Mid-Career Mentoring Award NIH K24 DK066144.

CM declares no conflicts of interest. MF has acted as a consultant for and/or receives research grant support from Roche, Merck, Vertex, Tibotec, Janssen, Bristol Myers squibb, Novartis, Salix, Gilead and Pharmasset. He also hold stocks in Pharmasset.

Miravirsen, a novel injectable drug targeting a “microRNA” known as miR-122 responsible for the accumulation of hepatitis C virus (HCV) in the liver, had long-lasting activity against the virus when used without other medications in a preliminary clinical trial presented Monday, November 7, at the 62nd annual meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco.

New clinical data from the early stage Phase II study demonstrate that four out of nine participants treated with the highest dose of miravirsen—7 milligrams per kilogram (mg/kg) of body weight—saw their HCV viral loads decrease to undetectable levels with just four weeks of treatment.

These findings, said study presenter Harry Janssen, MD, PhD, of Erasmus MC University Hospital in Rotterdam, Netherlands, suggest that miravirsen’s unique mechanism-of-action offers a high barrier to viral resistance and the potential for cure, used either alone or with other medications. He also noted that miravirsen was well tolerated in people living with HCV, signaling a possible advantage over today’s standard pegylated interferon–based treatment.

Only about one in five sexually active high school students has ever been tested for HIV, CDC researchers reported.

Testing was more common among those who reported a behavior that increases their risk of acquiring the virus, Alexandra Balaji, PhD, and colleagues at the CDC.

But even in those subgroups, less than half of the students reported ever having had an HIV test, the group reported online in Archives of Pediatrics & Adolescent Medicine.

The findings come from an analysis of the 2009 national Youth Risk Behavior Survey, a nationally representative sample of students in grades 9 to 12 who attended public and private schools.

All told, 16,410 students returned usable data and slightly less than half -- 7,591 -- reported ever having had sexual intercourse. Among those, the researchers said, only 22.6% reported that they had been tested at any time for HIV (excluding tests done for blood donation).

The survey also asked a series of questions about risky behaviors, including such things as injection drug use, multiple partners, and condoms.

A multivariable analysis showed that, compared with those who did not report the risky behavior, the odds ratios for being tested were:

1.70 among the 3.7% who reported injection drug use (95% CI 1.14 to 2.56)

1.43 among the 13.9% who reported ever having been forced to have sex (95% CI 1.19 to 1.72)

1.28 among the 36.2% who reported not using a condom during their most recent sexual intercourse (95% CI 1.08 to 1.51)

2.32 among the 30.2% who reported four or more lifetime partners (95% CI 1.98 to 2.73)

In no case did the proportion reporting being tested exceed 42%.

The researchers cautioned that the study was cross-sectional, so that the temporal relationship between testing and risk behaviors could not be established.

As well, they noted, the data are self-reported and could have built-in biases, the survey did not ask about same-sex behavior which omits an important risk group, and the results only apply to adolescents attending high school.

The findings are "disturbing," commented Lawrence D'Angelo, MD, of the Children's National Medical Center in Washington, DC, in an accompanying editorial.

He noted that although CDC guidelines recommend HIV testing for all individuals ages 13 to 64 years, the American Academy of Pediatrics guidelines delay routine testing until age 16 and even then only in adolescents who live in communities where the overall prevalence of infection is greater than 0.1%.

Despite current recommendations, however, D'Angelo argued, "quite simply, we are not testing the right people and are not testing them enough."

He urged a more rigorous approach to HIV testing for adolescents, beginning with a universal test at age 13. Testing would be repeated annually in all adolescents at risk for HIV and again universally at 18, regardless of risk behaviors, followed by universal testing every three years afterward.

The study was supported by the CDC. Authors are employees of the agency.

Jan. 4, 2012, 9:00 a.m. EST

BALTIMORE, Jan 04, 2012 (BUSINESS WIRE) -- Profectus BioSciences, Inc., a leader in the development of therapeutic and preventive vaccines against infectious diseases, announced that a phase 1 study to test the safety and immunogenicity of a recombinant vesicular stomatitis virus (rVSV)-vectored HIV vaccine initiated on October 26th and, as of December 27th, 20 volunteers have been immunized. VSV is a type of RNA virus that can infect both insects and mammals. It is commonly used in laboratory settings as a gene delivery vector without the potential for integration, a characteristic that provides a safety advantage in vaccine applications. The first studies to demonstrate the potential of rVSV as an HIV vaccine vector were performed in the laboratories of Dr. John K. Rose at Yale University more than a decade ago. The recombinant version used in this new vaccine study is able to replicate in human cells, but has been attenuated (weakened) so as not to cause illness in animals or humans.

The novel rVSV vector, expressing the HIV-1 gag protein, is being evaluated in a trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The study is being conducted by the NIAID-funded HIV Vaccine Trials Network (HVTN) under a protocol designated HVTN 090.

The phase 1, placebo-controlled, dose-escalation study will enroll 60 HIV-uninfected adults. It will assess the safety and immunogenicity of increasing doses of the rVSV HIV-1 gag vaccine administered by intramuscular injection. Assays conducted by the HVTN Central Immunology Laboratories will measure the ability of the vaccine to induce both antibody and cell-mediated immune responses to the HIV gag protein. The vaccine was found to be safe and immunogenic in non-human primates, and is the first vaccine based on an rVSV platform to be tested in humans.

Dr. John Eldridge, Chief Scientific Officer, said: "Profectus is very pleased to announce the first clinical evaluation of the rVSV HIV-1 vaccine. This replication competent delivery vector provides both unique immunogenicity and the high manufacturing yields needed for an HIV vaccine intended for worldwide use."

About the rVSV HIV-1 gag vaccine

The rVSV HIV-1 gag vaccine consists of an attenuated replication competent form of the Indiana serotype of rVSV that expresses the HIV-1 gag protein. The vaccine was designed to elicit a robust cell mediated immune response to the HIV-1 gag protein, and will be supplied in frozen formulation to this proof-of-concept study. Ongoing studies are examining the potential to develop a lyophilized formulation that will replace the frozen form, and greatly simplify distribution of vaccine to the developing world.

About NIAID

NIAID conducts and supports research--at NIH, throughout the United States, and worldwide--to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov/ .

About the HVTN

The HIV Vaccine Trials Network (HVTN) is an international collaboration of scientists and educators searching for an effective and safe HIV vaccine. The HVTN's mission is to facilitate the process of testing preventive vaccines against HIV/AIDS. The HVTN conducts all phases of clinical trials, from evaluating experimental vaccines for safety and the ability to stimulate immune responses, to testing vaccine efficacy. Support for the HVTN is provided through a cooperative agreement from the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health (NIH). The Network's HIV Vaccine Trial Units are located at leading research institutions in 27 cities on four continents. Internationally renowned HIV vaccine and prevention researchers lead the units.

About Profectus BioSciences, Inc.

Profectus BioSciences, Inc. is a technology based vaccine company devoted to the treatment and prevention of infectious disease and related cancer, with the goal of reducing morbidity and mortality. Since its inception in 2003, the Company's strategic intent has been to acquire and develop the technologies needed to achieve this goal. The Company has licensed a group of vaccine-based technologies from Wyeth Vaccines (now Pfizer, Inc.) that greatly enhance the immunogenicity of prophylactic and therapeutic vaccines based on a "prime-boost" strategy. This strategy uses the delivery of a best-in-class pDNA vaccine to "prime" the immune system, followed by a first-in-class "boost" with an rVSV vector. Current disease and virus targets include hepatitis C virus (HCV), human papilloma virus (HPV), herpes simplex virus type 2 (HSV-2), human immunodeficiency virus (HIV), Ebola virus, Marburg Virus, and malaria. The Profectus rVSV HIV-1 vaccine program has been supported through the award of a $22.5M HIV Vaccine Design and Development Teams (HVDDT) contract HHSN272200800061C from the NIH that has supported the research, development, and manufacturing costs of the rVSVIN HIV-1 gag vaccine.

NEW HAVEN, Conn., Jan. 4, 2012 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN), a leader in the discovery and development of small molecule drugs to combat the most challenging infectious diseases, announced today the receipt of a Fast Track designation from the U.S. Food and Drug Administration (FDA) for ACH-1625 for the treatment of chronic hepatitis C virus (HCV). ACH-1625 is a once-daily protease inhibitor with broad genotypic coverage against HCV that was discovered by Achillion and is currently being evaluated in a Phase 2 clinical trial.

Fast Track designation was granted to ACH-1625 for its potential to provide:

- Improved safety and tolerability as compared to the current standard of care;

- Convenient once-daily dosing;

- Broader genotypic coverage of HCV;

- An improved drug-drug interaction profile with greater potential to treat HCV patients with comorbidities, co-infected with HIV, or pre- or post-liver transplantation; and

- Development in a once-daily interferon-free oral combination.

"We are very pleased with the granting of a Fast Track designation for ACH-1625, which we believe highlights this protease inhibitor's attributes which include broad genotypic coverage of HCV, once-daily administration and an improved safety, efficacy and tolerability profile over currently approved therapies for HCV," commented Michael Kishbauch, President and Chief Executive Officer of Achillion. "As we work toward achieving our near-term milestones, we remain eager to initiate an interferon-free, all-oral combination clinical study evaluating our protease inhibitor plus NS5A inhibitor for the treatment of HCV during the second half of this year."

Under the FDA Modernization Act of 1997, the Fast Track program facilitates interactions with the FDA before and during the submission of a New Drug Application (NDA) for therapeutics being investigated as a treatment of serious or life-threatening diseases which demonstrate the potential to address an unmet medical need for such a condition. The Fast Track program enables a company to file an NDA on a rolling basis as data becomes available. This permits the FDA to review the filing as it is received, rather than waiting for the entire document prior to commencing the review process. With a Fast Track designation, there is an opportunity for more frequent interactions with the FDA and the possibility of a priority review, which could decrease the typical development time and review period.

About ACH-1625

ACH-1625 is a HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. ACH-1625 has rapid and extensive partitioning to the liver, as well as high liver/plasma ratios. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50 of approximately 1nM.

In the first segment of a Phase 2a clinical study, treatment-naïve genotype 1 HCV patients received doses of 200 mg, 400 mg, or 800 mg of ACH-1625 in combination with pegylated interferon and ribavirin (SOC) and achieved a rapid viral response (RVR) of 75 — 81% compared to an RVR of 20% for patients receiving SOC only. ACH-1625 was well tolerated at all doses with no serious adverse events reported and adverse events which were reported as mild to moderate and transient. The second segment of this Phase 2a, randomized, double-blind trial is evaluating the safety, tolerability and antiviral activity of once daily ACH-1625, at doses of 200 mg, 400 mg or 800 mg, in combination with SOC for 12 weeks of dosing. The primary endpoint for this trial is complete early virological response (cEVR). Following 12 weeks of therapy, patients will continue to receive an additional 12 weeks of pegylated interferon alfa-2a and ribavirin and be eligible to discontinue treatment at week 24 if they achieve extended rapid virologic response (eRVR) at week 12. Patients who do not achieve an eRVR will continue to receive SOC until week 48.

About HCV

The hepatitis C virus infects the liver and is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80 percent of individuals become chronically infected following exposure to the virus. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and an injectable route of administration.

About Achillion Pharmaceuticals

Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease including hepatitis C and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000 begin_of_the_skype_highlighting 1-203-624-7000 end_of_the_skype_highlighting.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements, including statements with respect to the potency, safety and tolerability over currently-approved therapies, increased effectiveness and other characteristics of ACH-1625, Achillion's expectations regarding timing for the commencement, completion and reporting of results from clinical trials of Achillion's protease inhibitors, and the potential benefits of Fast Track designation for ACH-1625. Among the important factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things: Achillion's ability to: replicate in later clinical trials positive results found in earlier stage clinical trials of ACH-1625 and its other product candidates; advance the development of its drug candidates under the timelines it anticipates in current and future clinical trials; obtain necessary regulatory approvals; obtain patent protection for its drug candidates, and the freedom to operate under third party intellectual property; establish commercial manufacturing arrangements and to identify, enter into and maintain collaboration agreements with appropriate third-parties; compete successfully with other companies that are seeking to develop improved therapies for the treatment of HCV; and raise the substantial additional capital needed to achieve its business objectives. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2010 and its subsequent SEC filings.

In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any obligation to update any forward-looking statement, except as required by applicable law.

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